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Targeting the senescent surfaceome through DPP4 antibody-functionalized nanoparticles. An application to cancer
Blanca Escriche-Navarro1, Eva Garrido2, Andrea Escudero3
1Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM) Universitat Politècnica de València, Universitat de València, Camino de Vera, s/n, 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, 28029, Madrid, Spain; Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica de València, IIS La Fe. Av. Fernando Abril Martorell, 106 Torre A 7(a) Planta, 46026, Valencia, Spain.
Abstract:
Due to the heterogeneity of the senescent phenotype and the lack of a universal biomarker of senescence, the targeting of senescent cells is still an unresolved challenge, and the elimination of senescent cells using specific drugs (senolytics) is still limited in clinical use due to the off-target effects and associated toxicities of current therapeutic strategies. In this study, the induction of senescence in human melanoma cells by palbociclib is found to lead to a senescent phenotype characterized by overexpression of the membrane protein dipeptidyl peptidase 4 (DPP4), previously identified only in ageing contexts. Based on this discovery, a nanoparticle targeting DPP4 overexpression in the senescent surfaceome is designed, synthesized, and characterized to target senescent cancer cells. The nanoparticle based on mesoporous silica is loaded with the senolytic navitoclax, coated with disulfide-containing poly(ethylene glycol) to generate a redox-sensitive gatekeeper (S-S-PEG), and functionalized with an antibody against the DPP4 protein. The ability of the nanoparticles to effectively detect and eliminate senescent cells was confirmed in vitro and in vivo using a mouse model of palbociclib-induced senescent in melanoma. The DPP4-targeted nanoparticle effectively reduces tumor growth and selectively removes senescent cells. Taken together, this study highlights the potential of surfaceome-targeted nanoparticles, as a clinically relevant strategy for improving senolytic therapies.
Insights
Researchers developed a novel nanoparticle to target senescent melanoma cells by identifying dipeptidyl peptidase 4 (DPP4) as a senescence biomarker. This targeted approach effectively eliminates senescent cells and reduces tumor growth, offering a promising senolytic therapy.
Area of Science:
- Biomedical Engineering
- Oncology
- Cell Biology
Background:
- Targeting senescent cells (senolytics) faces challenges due to heterogeneous phenotypes and lack of universal biomarkers.
- Current senolytic strategies are limited by off-target effects and toxicity, hindering clinical application.
Purpose of the Study:
- To develop a targeted nanoparticle for eliminating senescent cancer cells.
- To identify and utilize dipeptidyl peptidase 4 (DPP4) as a biomarker for senescent cells.
Main Methods:
- Senescence was induced in human melanoma cells using palbociclib.
- A mesoporous silica nanoparticle was designed, loaded with navitoclax, and functionalized with anti-DPP4 antibodies.
- In vitro and in vivo studies in a mouse model were conducted to evaluate nanoparticle efficacy.
Main Results:
- Palbociclib-induced senescence in melanoma cells showed overexpression of DPP4.
- The DPP4-targeted nanoparticles selectively detected and eliminated senescent cells.
- Nanoparticle treatment effectively reduced tumor growth in vivo.
Conclusions:
- DPP4 is a viable biomarker for targeting senescent cells in melanoma.
- Surfaceome-targeted nanoparticles offer a promising strategy for improving senolytic therapy.
- This approach demonstrates potential for enhanced senolytic efficacy with reduced toxicity.
